Analysis of most hematologic neoplasms indicates the involvement of one or more cell lineages in the bone marrow and/or the blood but rules out the involvement of all lineages in any one neoplasm. It is important to detect lineage involvement in order to clarify which stem cells are involved in leukemia, to predict prognosis, and to select appropriate treatment. Our aim was to study the cell lineage involvement of some of the recurrent chromosomal abnormalities seen in hematological neoplasms. The direct morphology-antibody-chromosomes (MAC) method was used. The deletion 20q in myeloproliferative diseases (MPD), the deletion of 5q and t(1;7) in myelodysplastic syndromes (MDS), and t(3;3) in acute myeloid leukemia subtype M7 (AML-M7) were seen in all or at least in two myeloid lineages. These were interpreted as stem cell abnormalities. Deletion 13q in MPD, t(8;21) in AML-M2 and t(15;17) in AML-M3 were seen in granulocytic lineages only; t(14;18) in non-Hodgkin's lymphoma and trisomy 12 as the sole abnormality in chronic lymphocytic leukemia (B-CLL) were seen only in immunoglobulin light chain clonal B cells; inversion 14 in T-CLL was seen only in T cells, whereas t(15;14) in acute lymphocytic leukemia with eosinophilia (ALL-EO) was seen in lymphoid stem cells but not in mature granulocytes or lymphocytes. Additional abnormalities (in addition to the Philadelphia chromosome) in chronic myeloid leukemia (CML) were seen in all myeloid cell lineages and also in mature granulocytes, B cells, and large granular lymphocytes. Abnormalities in Hodgkin's disease were restricted to CD30-positive Reed-Sternberg cells. Trisomy 8 and monosomy 7 are abnormalities that may be present in either stem cells or any of the single cell lineages.

Despite the advances in understanding the biology of hematologic neoplasms which has resulted in the approval of new drugs, the therapeutic options are still scarce for relapsed/refractory patients. Eribulin is a unique microtubule inhibitor that is currently being used in the therapy for metastatic breast cancer and soft tissue tumors. Here, we uncover eribulin's cellular and molecular effects in a molecularly heterogeneous panel of hematologic neoplasms. Eribulin reduced cell viability and clonogenicity and promoted apoptosis and cell cycle arrest. The minimal effects of eribulin observed in the normal leukocytes suggested selectivity for malignant blood cells. In the molecular scenario, eribulin induces DNA damage and apoptosis markers. The ABCB1, ABCC1, p-AKT, p-NFκB, and NFκB levels were associated with responsiveness to eribulin in blood cancer cells, and a resistance eribulin-related target score was constructed. Combining eribulin with elacridar (a P-glycoprotein inhibitor), but not with PDTC (an NFkB inhibitor), increases eribulin-induced apoptosis in leukemia cells. In conclusion, our data indicate that eribulin leads to mitotic catastrophe and cell death in blood cancer cells. The expression and activation of MDR1, PI3K/AKT, and the NFκB-related targets may be biomarkers of the eribulin response, and the combined treatment of eribulin and elacridar may overcome drug resistance in these diseases.

During lymphocyte development, a diverse repertoire of lymphocyte antigen receptors is produced to battle against pathogens, which is the basis of adaptive immunity. The diversity of the lymphocyte antigen receptors arises primarily from recombination-activated gene (RAG) protein-mediated V(D)J rearrangement in early lymphocytes. Furthermore, transcription factors (TFs), such as early B cell factor 1 (EBF1), paired box gene 5 (PAX5), and proto-oncogene myelocytomatosis oncogene (MYC), play critical roles in regulating recombination and maintaining normal B cell development. Therefore, the aberrant expression of these TFs may lead to hematologic neoplasms.

ASXL1 (additional sex combs like 1) is a gene that is mutated in a number of hematological neoplasms. The most common genetic alteration is c.1934dupG p.Gly646fs. Previous publications have shown that ASXL1 mutations have a negative prognostic impact in patients with MDS and AML, however, controversy exists regarding the molecular testing of ASXL1 c.1934dupG as polymerase splippage over the adjacent homopolymer could lead to a false-positive result. Here, we report the first study to systematically test different targeted next generation sequencing (NGS) approaches for this mutation in patients with hematologic neoplasms. In addition, we investigated the impact of proofreading capabilities of different DNA polymerases on ASXL1 c.1934dupG somatic mutation using conventional Sanger sequencing, another common method for ASXL1 genotyping. Our results confirm that ASXL1 c.1934dupG can be detected as a technical artifact, which can be overcome by the use of appropriate enzymes and library preparation methods. A systematic study of serial samples from 30 patients show that ASXL1 c.1934dupG is a somatic mutation in haematological neoplasms including MDS, AML, MPN and MDS/MPN and often is associated with somatic mutations of TET2, EZH2, IDH2, RUNX1, NRAS and DNMT3A. The pattern of clonal evolution suggests that this ASXL1 mutation might be an early mutational event that occurs in the principal clonal population and can serve as a clonal marker for persistent/relapsing disease.

No large US population-based study focusing on recent decades, to our knowledge, has comprehensively examined risks of second malignant solid and hematological neoplasms (solid-SMN and heme-SMN) after testicular cancer (TC), taking into account initial therapy and histological type.

Although several epigenetic drugs have been reported to have therapeutic efficacy for some hematologic neoplasms (HNs) in clinical trials, few achieved disease-free survival benefit. The traditional drug discovery pathway is costly and time-consuming, and thus, more effective strategies are required. We attempted to facilitate epigenetic drug repositioning for therapy of HNs by screening the Human Epigenetic Drug Database (HEDD) in the web, conducting a bench-work cytotoxicity test and a retrospective nationwide cohort study prior to a clinical trial.

Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors are a promising source of cell therapy. However, their effectiveness in cancer remains less known. This study is the first to evaluate the quality of BM-MSCs obtained from young and elderly healthy volunteers (KNT cells). The KNT cells had normal karyotypes and were positive for MSC markers (CD90, CD73, CD105). When cultured under appropriate conditions, they showed adipogenic or osteogenic potential. Hence, the anti-neoplastic effects of secretory factors [supernatant or extracellular vesicles (EV)] from KNT cells were verified using several neoplastic cells (three multiple myeloma, three myeloid leukemia, and three lymphoma cell lines). The conditioned medium (CM), but not EV, of KNT cells derived from young healthy donors significantly inhibited myeloma and lymphoma cell proliferation, but enhanced myeloid leukemia proliferation. Anti-angiogenesis effect of CM and EV derived from young KNT against hematologic neoplasia-induced angiogenesis was evident and more prominent in CM than in EV but not evident in elderly KNT-derived EV. These findings indicate that the anti-tumor effect of KNT cells depends on the types of hematologic neoplasia, with elements existing in the supernatant and not in EVs. Therefore, BM-MSC may produce soluble factors that affect cell proliferation of neoplasia, causing cell-to-cell communication. The anti-angiogenesis effect of KNT cells depends on the age of BM-MSC donors.

Sex chromosome loss (SCL), including loss of an X chromosome (-X) in females and loss of the Y chromosome (-Y) in males, resulting in a karyotype of 45,X, rarely occurs in patients post an allogeneic hematopoietic stem cell transplant (alloHSCT). However, origin of this abnormal clone and its clinical significance remains unknown.

We conducted this study with the objective of elucidating the mechanism of development of fibrosis in hematologic neoplasms and develop treatments for these patients. Among the suggested mechanisms of development of fibrosis is cases of hematologic neoplasms is the production of TGF-beta1 (transforming growth factor-beta-1) and TNF-alpha1 (tumor necrotizing factor-alpha-1) by the tumor cells, both of which are fibrosis-stimulating cytokines that act on fibroblasts to promote fibrosis. However, there are few reports based on human clinical pathology studies. We conducted an immunohistochemical study on paraffin-embedded formalin-fixed specimens obtained from 104 patients with various pathologic conditions (acute leukemia, malignant lymphoma, inflammation, cancer, etc.). The association of tissue fibrosis with positive immunohistochemistry for TGF- beta1 and/or TNF-alpha1, TGF-beta1 was found to be strongly associated with tissue fibrosis, and in cases with positive immunohistochemistry for TGF-beta1, the odds ratio for fibrosis was 12.8, which was significantly high. Combined positivity for TGF-beta1 and TNF-alpha1 was also associated with a significant odds ratio for fibrosis of 3.4, suggesting that TGF-beta1 expression is an important prerequisite. TGF-beta1 has been suggested as playing a relatively important role in tissue fibrosis. Future clinical application of these cytokines for both diagnosis and treatment is expected.

By means of a mail questionnaire, information on a series of 56 pregnancies i in 48 women diagnosed with leukemia or lymphoma was collected from ten hospitals. Seven patients conceived while receiving treatment for their neoplasms; in 22 patients, the hematologic disease was diagnosed during pregnancy, and the remaining 27 patients became pregnant after completion of the antineoplastic treatment. When a comparison was made of the evolution of these pregnancies to that of pregnancies in a healthy population, no increase in the incidence of complications was observed: 64% of the pregnancies went to term, 9% resulted in spontaneous abortion, and 5% resulted in premature births. The observed incidence of one major malformation in 56 pregnancies did not differ from the frequency of malformations in the offspring of healthy individuals. There were no fetal losses in six pregnancies in which conception occurred during the first year after chemotherapy. In spite of the inherent limitations derived from the design of this type of study and the type of subject analyzed, the data here support the hypothesis that the cytostatic treatment of hematologic malignancies, if deemed necessary, should not be postponed because of pregnancy. Moreover, the authors agree with advice recommending that no antifolic or alkylating agents be used for prolonged periods and that radiotherapy be avoided, especially to those fields involving the pelvic area.

BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, are essential for BCR-ABL1+, but not WT, pre-B-cell proliferation. The mitogen-activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (ERK) pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient's outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.

We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.

Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene. These mutations were then tracked backwards in marrow samples preceding secondary leukemia occurrence, using pyrosequencing and a NGS protocol that allows the detection of low variant allele frequencies (≥0.1%).Somatic mutations were detectable in the BM harvested at the primary diagnosis, prior to any cytotoxic treatment in three patients, while they were not detectable and apparently acquired by the t-MN clone in five patients.These data show that clonal evolution in t-MN is heterogeneous, with some somatic mutations preceding cytotoxic treatment and possibly favoring leukemic development.

Hematologic malignancies such as leukemias and lymphomas are among the leading causes of pediatric cancer death worldwide, and although survival rates have improved with conventional treatments, the development of drug-resistant cancer cells may lead to patient relapse and limited possibilities of a cure. Drug-resistant cancer cells in these hematologic neoplasms are induced by overexpression of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein families, such as Bcl-XL, Bcl-2, and Mcl-1. We have previously shown that peptides from the BH3 domain of the proapoptotic Bax protein that also belongs to the Bcl-2 family may antagonize the antiapoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. Furthermore, cell-permeable Bax BH3 peptides also elicit antitumor activity and extend survival in a murine xenograft model of human B non-Hodgkin's lymphoma. However, the activity of the BH3 peptides of the proapoptotic Bak protein of the Bcl-2 family against these hematologic malignant cells requires further characterization. In this study, we report the ability of the cell-permeable Bak BH3 peptide to restore apoptosis and induce chemosensitization of acute lymphoblastic leukemia and non-Hodgkin's lymphoma cell lines, and this event is enhanced with the coadministration of cell-permeable Bax BH3 peptide and represents an attractive approach to improve the patient outcomes with relapsed or refractory hematological malignant cells.

Hematologic malignancies cause more than half a million deaths every year worldwide. Analgesics were suggested as chemopreventive agents for several cancers but so far, results from individual studies about the relationship between paracetamol (acetaminophen) use and hematologic malignancies are conflicting. Therefore, we decided to perform a systematic review and meta-analysis. We retrieved studies published in any language by systematically searching Medline, Embase, Conference Proceedings Citation Index, Open Access Theses and Dissertations, and the five regional bibliographic databases of the World Health Organization until December 2020. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated according to the inverse of their variances. We performed separate analyses by histologic type. We also evaluated publication bias and assessed quality. A total of 17 study units met our inclusion criteria. The results show an association of hematologic malignancies with any paracetamol intake (OR 1.49, 95% CI 1.23-1.80) and with high paracetamol intake (OR 1.77, 95% CI 1.45-2.16). By subtype, risk was higher for multiple myeloma (OR 2.13, 95% CI 1.54-2.94) for any use and OR 3.16, 95% CI 1.96-5.10 for high intake, while risk was lower and non-significant for non-Hodgkin lymphoma. This meta-analysis provides evidence that paracetamol intake may be associated with hematologic malignancies and suggests that a dose-response effect is plausible. These results are unlikely to be due to publication bias or low quality of studies. Future research should focus on assessing the dose-response relationship.

Germline mutation in GATA2 can lead to GATA2 deficiency characterized by a complex multi-system disorder that can present with many manifestations including variable cytopenias, bone marrow failure, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), and severe immunodeficiency. Penetrance and expressivity within families is often variable. There is a spectrum of bone marrow disease in symptomatic cytopenic patients ranging from hypocellular marrows without overt dysplasia to those with definitive MDS, AML, or chronic myelomonocytic leukemia. Relatives of probands with the same mutations may demonstrate minimal disease manifestations and normal marrows. A comprehensive clinical, hematological and genetic assessment of 25 patients with germline GATA2 mutation was performed. MDS-associated mutations were identified in symptomatic GATA2 patients both with overt MDS and in those with hypocellular/aplastic bone marrows without definitive dysplasia. Healthy relatives of probands harboring the same germline GATA2 mutations had essentially normal marrows that were overall devoid of MDS-associated mutations. The findings suggest that abnormal clonal hematopoiesis is a common event in symptomatic germline mutated GATA2 patients with MDS and also in those with hypocellular marrows without overt morphologic evidence of dysplasia, possibly indicating a pre-MDS stage warranting close monitoring for disease progression.

Myeloid malignancies are characterized by an extreme molecular heterogeneity, and many efforts have been made in the past decades to clarify the mechanisms underlying their pathogenesis. In this scenario SET binding protein 1 (SETBP1) has attracted a lot of interest as a new oncogene and potential marker, in addition to its involvement in the Schinzel-Giedon syndrome (SGS). Our review starts with the analysis of the structural characteristics of SETBP1, and extends to its corresponding physiological and pathological functions. Next, we describe the prevalence of SETBP1 mutations in congenital diseases and in hematologic malignancies, exploring how its alterations might contribute to tumor development and provoke clinical effects. Finally, we consider to understand how SETBP1 activation could be exploited in molecular medicine to enhance the cure rate.

Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.

The aim of this systematic review is to give an update of all currently available evidence on the relevance of a geriatric assessment in the treatment of older patients with hematologic malignancies. A systematic search in MEDLINE and EMBASE was performed to find studies in which a geriatric assessment was used to detect impaired geriatric domains or to address the association between geriatric assessment and survival or clinical outcome measures. The literature search included 4,629 reports, of which 54 publications from 44 studies were included. Seventy-three percent of the studies were published in the last 5 years. The median age of the patients was 73 years (range, 58-86) and 71% had a good World Health Organization (WHO) performance status. The median prevalence of geriatric impairments varied between 17% and 68%, even in patients with a good WHO performance status. Polypharmacy, nutritional status and instrumental activities of daily living were most frequently impaired. Whereas several geriatric impairments and frailty (based on a frailty screening tool or summarized geriatric assessment score) were predictive for a shorter overall survival, WHO performance status lost its predictive value in most studies. The association between geriatric impairments and treatment-related toxicity varied, with a trend towards a higher risk of (non-)hematologic toxicity in frail patients. During the follow-up, frailty seemed to be associated with treatment non-completion, especially when patients were malnourished. Patients with a good physical capacity had a shorter stay in hospital and a lower rate of hospitalization. Geriatric assessment, even in patients with a good performance status, can detect impaired geriatric domains and these impairments may be predictive of mortality. Moreover, geriatric impairments suggest a higher risk of treatment-related toxicity, treatment non-completion and use of healthcare services. A geriatric assessment should be considered before starting treatment in older patients with hematologic malignancies.